Multiple inputs and controls participate in the maintenance of energy homeostasis, and numerous neural and endocrine systems are involved in the integrated responses that maintain energy stores in the body at a level. Since most stored energy is in the form of adipose tissue (fat), and since the brain is the major controller of energy homeostasis, a fundamental requirement is that the brain receive accurate and timely information about the amount and distribution of body fat. This information is then integrated with other factors to determine whether an individual seeks and eats food (i.e., energy intake), as well as the efficiency with which the ingested food is utilized (energy expenditure) or stored. Information regarding the amount of fat stored in the body reaches the brain via the circulating signals insulin and leptin. Each is secreted into the blood in direct proportion to total body fat, and each is transported from the blood into the brain where it interacts with neurons situated to influence energy intake and expenditure. Hence, insulin and leptin are considered to be adiposity signals, and the long-term goal of this project is to elucidate how adiposity signals interact with other factors to influence energy homeostasis. We anticipate that the coming decade will see considerable progress in this arena, as well as the translation of the new-found information into potential novel therapeutic strategies to tackle clinical problems of dysregulation of energy homeostasis (i.e., obesity, eating disorders). With this as an ultimate end point, the present proposal has three specific aims that address critical and as yet unanswered questions regarding the actions of adiposity signals in the brain. The first assesses the hypothesis that insulin and leptin act in the hypothalamus by enhancing the signal provided by local levels of nutrients, including glucose and fatty acids. The second assesses several hypotheses following from our observation that there are important gender differences in the actions of insulin and leptin in the central control of energy homeostasis, and that males and females utilize different strategies to regulate energy homeostasis and defend their body fat stores. The final aim assesses hypotheses regarding the effect of reducing insulin signaling in specific brain regions on food intake and body weight, and upon related levels of metabolic hormones and neuropeptides, utilizing lentiviral technology.